Throughout this application various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
It has long been known that acridine derivatives, particularly 9-aminoacridines, bind preferentially to nucleic acids in living cells. Many anilinoacridine derivatives, for example, have been synthesized and were demonstrated to have outstanding experimental antitumor activity and a broad spectrum of biological activities Cain et al., J. Med. Chem. 1971; 14:311. Among these compounds, amsacrine [4'-(9-acridinylamino)methanesulfon-m-anisidide, m-AMSA] was reported to have high activity against the L1210 leukemia Cain et al., J. Med. Chem. 1975; 18:1110 and against a spectrum of experimental tumors Corbett et al., Cancer, 1977; 40:2660; Goldin et al., Eur. J. Cancer, 1981; 17:129. The clinically useful m-AMSA is an extremely promising drug in the treatment of leukemia Legha et al., Ann. Internal. Med., 1980; 93 (part 1):17 and malignant lymphoma Cabanillas et al., Blood, 1981; 57:614, particularly in combination with other cytotoxic agents Arlin et al., Cancer Res., 1980; 40:3304; Laster et al., Proc. Am. Ass. Cancer Res., 1980; 21:271. The drug, though, was inactive against a number of solid tumors during Phase II trials Casper et al., Cancer Treat. Rep., 1980; 64:345. m-AMSA is a DNA intercalator and topoisomerase II inhibitor Nelson et al., Proceedings of the National Academy of Science, 1984; 81:1361; Pommier et al., Cancer Res., 1985; 45:3143. The cytotoxicity of m-AMSA later revealed that this agent induced chromosomal aberrations and DNA damage Wilson et al., Cancer Res., 1984; 44:4420.
9-Anilinoacridines undergo nucleophilic attack by thiols to produce inactive products forming protein adducts linked by a thiol group to the C-9 position of the acridine and released side-chain Khan et al., Proc. Am. Ass. Cancer Res., 1980; 21:306. The half life of m-AMSA in the presence of fresh mouse blood at 37.degree. C. is about 23 minutes. More recently, an alternative mechanism was suggested for degradation of m-AMSA by mammalian liver extracts, in which the anilino ring is oxidized to a quinoneimine, then conjugated with glutathione to form the inactive 5'-thio metabolite Shoemake et al., Drug Metab. Disp., 1982; 10:35. The inventors have synthesized 3-(9-acridinylamino)-5-hydroxymethylaniline derivatives, in which, with both amino and hydroxymethyl functions in meta-position to 9-acridinylamino, it would not be possible to form a quinoneimine open for the nucleophilic attack of glutathione. These compounds would thus be tolerant under biological degradation. The inventors discovered that the derivatives of 3-(9-acridinylamino)-5-hydroxymethylanine are inhibitors of DNA topoisomerase II and show inhibition of tumor growth in vitro and in vivo (Tables 1 and 2). On the basis of the above considerations and discoveries, the present invention is submitted.